Pulmonary　fibrosis　(PF)　is　a　chronic　lung　disease　characterizedby　excess　extracellular　matrix　deposition　and　prolonged　inflammationthat　fails　to　resolve　and　is　druggable.　Using　resolvins　and　theirprecursors　for　inflammation　resolution,　we　demonstrate　a　nano-enabledapproach　for　accomplishing　robust　antifibrotic　effects　in　bleomycin-or　engineered　nanomaterial-induced　mouse　and　rat　PF　models.　Targetingthe　lipid　peroxidation-triggered　NLRP3　inflammasome　and　NF-&　kappa;Bpathway　in　macrophages　and　the　ROS-mediated　TGF-&　beta;/Smad　and　S1Psignaling　in　epithelial　cells　results　in　these　potent　protective　effectsat　the　ng/mL　dosimetry.　We　further　develop　an　inhalable　biocompatiblenanoparticle　that　encapsulates　fish　oil,　a　chosen　resolvin　precursor,with　phosphatidylcholine　and　polyethylene　glycol　to　enhance　drug　permeabilityand　facilitate　crossing　the　mucosal　barrier,　forming　＂fish-oilsome＂　(FOS).　Oropharyngeal　aspiration　andinhalation　of　FOS　improved　the　anti-inflammatory　status,　histologicalcharacteristics,　and　pulmonary　function　in　fibrotic　lungs,　which　wasmechanistically　supported　by　transcriptomic　and　proteomic　analyses.Further,　scale-up　engineered　FOS　samples　with　the　desired　physicochemicalproperties,　anti-PF　efficacy,　and　in　vivo　biocompatibilitywere　validated　in　different　batch　sizes　(up　to　0.2　L/batch).　Thisstudy　provides　a　practical　and　translatable　approach　to　promotinginflammation　resolution　and　PF　treatment.